The distribution of theta-class glutathione S-transferases in the liver and lung of mouse, rat and human

Abstract

Two murine Theta-class glutathione S-transferases (GSTs), mGSTT1 and mGSTT2, have been cloned and sequenced. The murine cDNAs, together with the published sequences of the rat and human enzymes, were used to design oligonucleotide probes in order to determine the distribution of mRNA for these enzymes in the liver and lung of rat, mouse and human. The mRNA distribution was compared with that of enzyme protein determined with an antibody to rat GSTT2-2. Both the antibody and the oligonucleotide probes gave the same distribution patterns. Both enzymes were present at significantly higher concentrations in mouse tissues than in rat or human tissues. In mouse liver, both enzymes were localized in specific cell types and in nuclei. Although the distribution of GSTT2-2 in rat liver was similar to that seen in the mouse, GSTT1-1 was not localized in a specific cell type or in the nuclei of either rat or human liver. In the lungs, very high concentrations of the Theta enzymes were present in mouse-lung Clara cells and ciliated cells, with much lower levels in the Clara cells only of rat lung. Low levels of human transferase GSTT1-1 were detected in a small number of Clara cells and ciliated cells at the alveolar/ bronchiolar junction. The relative activities between species, and the cellular and sub-cellular distribution within the liver and lungs of each species, provides an explanation for the species-specificity of methylene chloride, a mouse-specific carcinogen activated by glutathione S-transferase GSTT1-1.

Evidence that human class Theta glutathione S-transferase T1-1 can catalyse the activation of dichloromethane, a liver and lung carcinogen in the mouse: Comparison of the tissue distribution of GST T1-1 with that of classes Alpha, Mu and Pi GST in human

“…Most significantly, GSTT1 was found to be present in only trace amounts in human lung. This observation is consistent with hybridization data in situ of Mainwaring et al [52], which suggested that in pulmonary tissue GSTT1 mRNA is restricted to Clara cells and to ciliated cells at the alveolar\bronchiolar junction.…”

“…The present paper and that of Mainwaring et al [52] suggest that human lung has little metabolic capacity to activate DCM. However, as liver, small intestine, kidney, pancreas, prostate and skeletal muscle express significant amounts of GSTT1 protein it is probable that these organs activate DCM.…”

“…Protein purification and measurement of transferase activity with ENPP and DCM have provided evidence that GST T1-1 is present in human liver and lung [2,52]. In the present investigation, antibodies raised against the human Histagged GSTT1 were used to demonstrate that substantial amounts of the GSTT1 subunit are expressed in liver and kidney.…”

Dissimilar Characteristics of N-Methyl-N-Nitrosourea-Initiated Foci and Tumors Promoted by Dichloroacetic Acid or Trichloroacetic Acid in the Liver of Female B6C3F1 Mice

“…CYP 4Al is an important enzymatic marker for peroxisomal proliferation, since its expression precedes the peroxisomal response and is coordinated with the transcription of the peroxisomal (3-oxidation enzymes (1,18,34). Human GST-TR, rat GST-P, and murine GST-pi belong to the pi class of GST and have immunologic cross-reactivity (15,23,40). Although their precise role in tumorigenesis is unclear, GST-pi enzymes are involved in the biotransformation of xenobiotics by catalyzing glutathione conjugation, and a number of them have been associated with cancer initiation and malignant transformation (15,40 …”

GSTT1 is Deregulated in Left Colon Tumors

“…It is located on 22q11.23 and codes for a 239 amino acid long enzyme which is crucial for metabolism of various carcinogens (Singh et al, 2008). Its main function is to catalyze the conjugation of glutathione to hydrophobic electrophiles (Mainwaring et al, 1996). This gene is polymorphic for a very common deletion which has been investigated in relation to various cancers.…”